Dissecting DNA damage signaling pathways for BRCA1 and BARD1 recruitment
Category: Research Poster
Author(s): Maria Ignatieff
Presenter(s): Maria Ignatieff
Mentors(s): Tingting Yao, Carolina Dos Santos Passos
Upon DNA double-stranded breaks (DSBs), cells initiate signaling cascades that recruit repair machinery, collectively known as the DNA damage response (DDR). Typically, these pathways are initiated by the ATM and ATR kinases, which recruit downstream DDR factors through phosphorylation of histone H2Ax and histone ubiquitin conjugation pathways. These factors include the Breast cancer type 1 susceptibility protein (BRCA1) and its binding partner, BRCA1-associated ring domain 1 (BARD1). Unexpectedly, we found that inhibiting ATM and ATR leads to BRCA1 and BARD1 relocalization in the nucleolus, specifically during the G2 phase of the cell cycle. Further inhibition of the E1 ubiquitin-activating enzyme prevents this nucleolar localization, suggesting a dependence on ubiquitin conjugation. These findings point to a non-ATM/ATR dependent mechanism for the recruitment of BRCA1 and BARD1 to the nucleolus, a site of ribosome biogenesis. This may reveal novel functions of BRCA1 and BARD1 beyond ATM/ATR-induced DDR pathways and provide new insights into breast cancer etiology.